The inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most common inflammatory pain. Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407). It has been estimated that almost 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom are over 60 years of age, and this is expected to increase to 40 million as the age of the population increases, making this a public health problem of enormous magnitude (Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook of Pain, 387-395). Most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies from intermittent episodes of back pain that occur throughout life to a severe chronic disease that attacks the spine, peripheral joints and other body organs.
Another type of inflammatory pain is visceral pain which includes pain associated with inflammatory bowel disease (IBD). Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered gastrointestinal (G1) disorders that cause pain include functional bowel disorder (FBD) and inflammatory bowel disease (IBD). These GI disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain. Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.
There is a critical medical need to identify new pharmaceutically active compounds that interfere with key steps of the inflammatory pain process and particularly for the treatment and/or prevention of arthritis pain and/or symptoms of arthritis pain.
Surprisingly we have found that administration of an anti-CGRP antibody is effective in prevention and/or treatment of inflammatory pain, arthritis pain and in particular osteoarthritis pain.
CGRP (calcitonin gene-related peptide) is a 37 amino acid neuropeptide which acts as a neurotransmitter in the central nervous system. It binds with high affinity to the CGRP receptor, Calcitonin receptor-like receptor (CRLR), activating adenylate cyclase and protein kinase A production.
Centrally penetrating spinally administered, small molecule selective CGRP antagonists have been shown to be useful in the treatment of neuropathic and nociceptive pain conditions (Adwanikar et al, Pain 2007) suggesting that removal of endogenous CGRP in the spinal cord has an antinociceptive effect. Additionally intrathecal administration of antiserum against CGRP has been shown to reduce nociceptive behaviour in rodent models of arthritis (Kuraishi, Y., et. al Neurosci. lett (1998) 92, 325-329).
Surprisingly we have found that administration of an anti-CGRP antibody is effective, with a peripheral site of action, in the prevention and/or treatment of inflammatory pain and in particular osteoarthritis pain when administered peripherally. This peripheral administration route provides a distinct advantage over the requirement to administer antibodies intrathecally or spinally, a more high risk and inconvenient procedure.